The purpose of this application is to examine the effects of estradiol on anxiety like behaviors and the effects of estradiol on Limbic-Hypothalamo-Pituitary-Adrenal axis (LHPA) activity in female rats that differ in their novelty seeking behavior. Based on their locomotor activity in a novel environment outbred rats are categorized as High responders (HR) or Low Responders (LR). HR and LR male rats differ basally in the patterns of expression of some stress related genes, and exhibit different patterns of glucocorticoid secretion and cFos expression in the emotional circuitry following exposure to an anxiogenic environment (Kabbaj & Akil 2001; Kabbaj et al. 2000). Some molecular differences in LHPA axis were responsible for males' HR and LR anxiety like behavior. Of interest, hippocampal glucocorticoid receptors (GR) play a major role in determining individual differences in "anxiety" responses (Kabbaj et al. 2000). Our preliminary data in females show that HR and LR rats, in their D1 cycle, exhibit similar anxiety like behavior as their HR and LR male counterpart-HR less "anxious" than LR. However, during proestrus there is an equalization of anxiety like behaviors of HR and LR females, in that LR rats behave like HR rats in the anxiety test. In this application we plan to verify the hypothesis that estradiol is implicated in this equalization of anxiety in HR and LR rats. We will also extend the behavioral observations in HR and LR females and describe their basal LHPA axis activity as well as neuronal activation following exposure to two behavioral tests of anxiety: the open field and the social interaction test. We will also explore the role of hippocampal GR in determining "anxiety" levels of HR and LR female rats. Throughout the studies female rats will be compared to their males' counterpart. Aim 1: Role of estradiol in determining individual differences in anxiety-responses: Different groups of ovariectomized female HR and LR rats will be examined for their anxiety like behaviors and LHPA axis activity 24h after one injection of estradiol (0, 2, 5 or 10 ug). Females will be compared to their male counterpart for all the behavioral and molecular measures. Aim 2: Role of hippocampal GR in determining individual differences in anxiety like behaviors in females: We will examine the effect of a GR antagonist (RU 38486) infused in the hippocampus on anxiety like behaviors of HR and LR ovariectomized females. Male rats will be used as positive controls.